CCR2
|
TAMs
|
CCR2 antagonist
|
Inhibits the recruitment of inflammatory monocytes, infiltration and M2-polarisation of TAMs
|
[34]
|
CCR2
|
TAMs
|
Anti-CCR2
|
Promotes epithelial‑to‑mesenchymal transition by upregulating matrix metalloproteinase‑2
|
[35]
|
CCR2
|
TAMs
|
CCR2 monoclonal antibody
|
Inhibits recruitment of monocytes
|
[36]
|
CSF-1
|
TAMs
|
CSF-1 receptor antagonist
|
Reprograms polarization of TAMs
|
[37]
|
IL-6
|
TAMs
|
Anti-IL-6
|
Blocks downstream effect of TAM products
|
[38]
|
IL-6
|
MDSCs
|
Anti-IL-6
|
IL-6 expression levels strongly correlate with an MDSC phenotype and chemotherapy response in HCC patients
|
[44]
|
chemokine (C-C motif) ligand 26
|
MDSCs
|
Blockade of chemokine (C-C motif) ligand 26
|
Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth
|
[45]
|
SSAO
|
MDSCs
|
SSAO inhibitors
|
May have an anti-tumor effect on HCC by inhibiting recruitment of CD11b+ and Gr-1+ cells and hindering angiogenesis
|
[46]
|
STAT3
|
MDSCs
|
Anti-STAT3
|
Inhibiting STAT3 can enhance the clinical efficacy of CAR-T cells in LM through modulation of L-MDSC
|
[47]
|
CCRK
|
MDSCs
|
Anti-CCRK
|
Hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G-csf expression to enhance polymorphonuclear MDSCs recruitment and tumorigenicity in HCC
|
[48]
|
CCL9/CCR1
|
MDSCs
|
Blockade of CCL9/CCR1
|
CCL9 secreted by splenic macrophages induces a CCR1‑dependent accumulation of MDSCs in the spleen in a murine H22 hepatoma model
|
[49]
|
ENTPD2/CD39L1
|
MDSCs
|
Blockade of ENTPD2/CD39L1
|
Hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5'-AMP, which promotes the maintenance of MDSCs by preventing their differentiation in HCC
|
[50]
|
PD-L1
|
MDSCs
|
PD-1 monoclonal antibody
|
PD-L1+ MDSCs could be used as a new biomarker of HCC
|
[51]
|
IL-18/TLR2
|
MDSCs
|
Blockade of IL-18/TLR2
|
IL-18 administration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL-18 in TLR2(-/-) mice decreased the proportion of MDSC
|
[52]
|
TGF-β/Axl/CXCL5
|
TANs
|
Blockade of TGF-β/Axl/CXCL5
|
The synergy of TGF-β and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue.
|
[72]
|
cortisol
|
TANs
|
Inhibition of cortisol
|
increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human
|
[73]
|
CXCR2/CXCL1
|
TANs
|
Blockade of CXCR2/CXCL1
|
The CXCR2-CXCL1 axis can regulate neutrophil infiltration into HCC tumor tissues and might represent a useful target for anti-HCC therapies
|
[74]
|
CXCL17
|
TANs
|
Anti-CXCL17
|
CXCL17 expression was associated with more CD68 and less CD4 cell infiltration
|
[75]
|
CXCR6
|
TANs
|
Anti-CXCR6
|
Human HCC samples expressing high levels of CXCR6 contained an increased number of CD66+ neutrophils and microvessels
|
[76]
|
miRNA-21
|
CAFs
|
MiRNA-21 inhibitor
|
High level of serum exosomal miRNA-21 was correlated with greater activation of CAFs and higher vessel density in HCC patients
|
[84]
|
CD24
|
CAFs
|
Anti-CD24
|
HGF and IL6 secreted by CAFs promoted the stemness properties of CD24+ HCC cells through the phosphorylation of STAT3
|
[85]
|
LOXL2
|
CAFs
|
Anti--LOXL2
|
The secreted LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation
|
[86]
|
PD-L1/IL6/STAT3
|
CAFs
|
Blockade of PD-L1/IL6/STAT3
|
HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6-STAT3-PDL1 signaling cascade
|
[87]
|
IL6/STAT3
|
CAFs
|
blockade of IL6/STAT3
|
IL-6 secreted by CAFs promotes stem cell-like properties in HCC cells by enhancing STAT3/Notch signaling
|
[88]
|
Keratin 19
|
CAFs
|
Anti-Keratin 19
|
Keratin 19 expression in HCC is regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis.
|
[89]
|
LSD1
|
CAFs
|
Anti-LSD1
|
LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem-like Cells
|
[90]
|
PD-1
|
Tregs
|
PD-1 monoclonal antibody
|
The ratio of CD4+CD127+ PD-1- T effector cells to CD4+Foxp3+PD-1+ Tregs was significantly increased following treatment with sorafenib
|
[114]
|
PD-1
|
Tregs
|
PD-1 monoclonal antibody
|
Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity
|
[115]
|
PD-1
|
Tregs
|
PD-1 monoclonal antibody
|
Sorafenib treatment enhanced functions of tumor-specific effector T cells as well as relieved PD-1-mediated intrinsic and Treg-mediated non-cell-autonomous inhibitions in tumor microenvironment
|
[116]
|
CTLA4
|
Tregs
|
CTLA4 monoclonal antibody
|
Leptin inhibited Treg activation and function in vitro, demonstrated by lower expression of TGF-β, IL-10, CTLA4 and GITR in Tregs
|
[117]
|
CTLA4
|
Tregs
|
CTLA4 monoclonal antibody
|
Tumor-induced regulatory DC subset suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production
|
[118]
|
TIM3
|
Tregs
|
TIM3 monoclonal antibody
|
Antibodies against TIM3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects
|
[119]
|
Lnc-Tim3
|
Tregs
|
Anti-Lnc-Tim3
|
Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity
|
[120]
|
TIM3
|
Tregs
|
TIM3 monoclonal antibody
|
TIM3 -1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients
|
[121]
|
TIM3
|
Tregs
|
TIM3 monoclonal antibody
|
-1516G/T polymorphism in the promoter region of TIM3 gene may affect the disease susceptibility and HCC traits associated with HBV infection
|
[122]
|
GITR
|
Tregs
|
GITR monoclonal antibody
|
Agonistic targeting of GITR can enhance functionality of HCC TIL and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC
|
[123]
|
GITR
|
Tregs
|
GITR monoclonal antibody
|
GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression in HCC.
|
[124]
|
ICOS
|
Tregs
|
ICOS monoclonal antibody
|
Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the HCCmicroenvironment and predict reduced survival
|
[125]
|
OX40
|
Tregs
|
OX40 monoclonal antibody
|
OX40 expression in HCC is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis
|
[126]
|
LAG3
|
Tregs
|
LAG3 monoclonal antibody
|
Antibodies against LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects
|
[119]
|